CN108659003A - A kind of preparation method of pharmaceutical composition that treating canker sore - Google Patents
A kind of preparation method of pharmaceutical composition that treating canker sore Download PDFInfo
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- CN108659003A CN108659003A CN201810334362.2A CN201810334362A CN108659003A CN 108659003 A CN108659003 A CN 108659003A CN 201810334362 A CN201810334362 A CN 201810334362A CN 108659003 A CN108659003 A CN 108659003A
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- ethyl acetate
- indoles
- canker sore
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- 208000020670 canker sore Diseases 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 150000002475 indoles Chemical class 0.000 claims description 7
- -1 1- (tertiary butyl) -7- Methyl-1H-indole Chemical compound 0.000 claims description 6
- BXGYYDRIMBPOMN-UHFFFAOYSA-N 2-(hydroxymethoxy)ethoxymethanol Chemical compound OCOCCOCO BXGYYDRIMBPOMN-UHFFFAOYSA-N 0.000 claims description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229960001866 silicon dioxide Drugs 0.000 claims description 6
- 239000012265 solid product Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- NLXFKDHULKLENC-UHFFFAOYSA-N 3,4-dihydro-2h-1,3-oxazine Chemical class C1NCC=CO1 NLXFKDHULKLENC-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000010813 municipal solid waste Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical class [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims 1
- 229910001148 Al-Li alloy Inorganic materials 0.000 claims 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 claims 1
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical compound [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims 1
- OVNJGBUSDSCWIL-UHFFFAOYSA-N tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate N,N-dimethylpyridin-4-amine Chemical compound CN(C1=CC=NC=C1)C.C(=O)(OC(C)(C)C)OC(=O)OC(C)(C)C OVNJGBUSDSCWIL-UHFFFAOYSA-N 0.000 claims 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 22
- 239000003814 drug Substances 0.000 description 12
- 241000700159 Rattus Species 0.000 description 10
- 208000025865 Ulcer Diseases 0.000 description 10
- 231100000397 ulcer Toxicity 0.000 description 10
- 235000011187 glycerol Nutrition 0.000 description 8
- 210000004400 mucous membrane Anatomy 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 5
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 101100120057 Rattus norvegicus Fgf1 gene Proteins 0.000 description 1
- 241000256856 Vespidae Species 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108010074496 rat smooth muscle actin Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation method of pharmaceutical composition that treating canker sore, this method includes following route：
Description
Technical field
The present invention relates to field of medicaments, and specifically, the present invention relates to a kind of pharmaceutical compositions for treating canker sore
Preparation method.
Background technology
Canker sore is most common disease in oral mucosal disease, and illness rate occupies the first place of oral mucosal disease.Canker sore
Have many characteristics, such as periodicity, recurrent, self limiting.The treatment of canker sore at present is mostly used glucocorticoid, anti-inflammatory agent etc., application
These drug therapies may cause the adverse reactions such as drug resistance, flora imbalance.The present invention is directed to overcome the problems, such as these, suction is developed
Receive drug that is better and playing a protective role to oral cavity.
Invention content
The purpose of the present invention is to provide a kind of preparation methods of pharmaceutical composition that treating canker sore.
In order to achieve the object of the present invention, the present invention provides a kind of preparation side of pharmaceutical composition that treating canker sore
Method, this method include the following steps：
Step A：It is molten to indoles 7- methyl formates and the mixing of the dichloromethane and triethylamine of 4-dimethylaminopyridine at 0 DEG C
Di-tert-butyl dicarbonate is added dropwise in liquid, adds liter room temperature reaction overnight, reaction finishes, and water is added, three times with dichloromethane extraction,
Combined dichloromethane phase, is washed with saturated nacl aqueous solution, and anhydrous sodium sulfate drying is concentrated to give 1- (tertiary butyl) -7- methyl -
1H- indoles -1,7- dicarboxylic esters
Step B：At 0 DEG C, it is added into the tetrahydrofuran of 1- (tertiary butyl) -7- Methyl-1H-indole -1,7- dicarboxylic esters
Lithium Aluminium Hydride adds and slowly rises 50 DEG C of reaction half an hour of room temperature, and reaction finishes, and reaction solution is poured into trash ice and saturation sodium sulphate is molten
In the mixture of liquid, stirs 15 minutes, be extracted with ethyl acetate three times, combined ethyl acetate phase is washed with saturated nacl aqueous solution
It washs, anhydrous sodium sulfate drying, concentration, excess carries out chromatogram purification through silicagel column and washed with ethyl acetate/petroleum ether gradient 20-50%
It is de-, obtain white solid product (1H- indoles -1,7- diyl) dimethanol
Step C：At 0 DEG C, to being added dropwise in the anhydrous tetrahydro furan of (1H- indoles -1,7- diyl) dimethanol and triphenylphosphine
Diisopropyl azodiformate adds liter room temperature reaction overnight, and reaction finishes, and is concentrated under reduced pressure, and residue adds water ethyl acetate
Three times, combined ethyl acetate phase is washed with saturated nacl aqueous solution for extraction, and anhydrous sodium sulfate drying, concentration, excess is through silicagel column
It carries out chromatogram purification to be eluted with ethyl acetate/petroleum ether gradient 10-20%, obtains white solid product 1H, 3H- [1,3] oxazines
And [5,4,3- happinesses] indoles
Preferably, this method further includes the following steps：It can be added as needed one or more pharmaceutically acceptable
Carrier, such as diluent, excipient, filler, sorbefacient, surfactant, and the dosage form of needs is made.
Drug of the present invention effectively can inhibit oral inflammation to react, and promote oral cavity tissue reparative regeneration, to accelerate oral cavity to burst
The agglutination of ulcer has the potentiality for the treatment of canker sore, is expected to become the new medicine for the treatment of canker sore.
Description of the drawings
Fig. 1 is two groups of different time rat canker sore area variations.
Fig. 2 is two groups of different time rat canker sore FGF1 and α-SMA expression observations.
Specific implementation mode
In order to make those of ordinary skill in the art be better understood from the present invention, it is expanded on further this by the following examples
Effect of the invention drug in terms for the treatment of canker sore.
The preparation route of experimental example 1 1H, 3H- [1,3] oxazines simultaneously [5,4,3- happinesses] indoles：
Step 1：1- (tertiary butyl) -7- Methyl-1H-indole -1,7- dicarboxylic esters
At 0 DEG C, to indoles 7- methyl formates (5.00g, 0.029mol) and 4-dimethylaminopyridine (0.35g,
Dichloromethane (100mL) 0.003mol) and triethylamine (8mL) mixed solution and dripping di-tert-butyl dicarbonate (8.81g,
0.15mol), liter room temperature reaction is added overnight.Reaction finishes, and water is added, three times with dichloromethane extraction, combined dichloromethane
Phase is washed with saturated nacl aqueous solution, and anhydrous sodium sulfate drying is concentrated to give target product (7.50g, 95.4%).
1H NMR(400MHz,CDCl3,)δ1.65(s,9H),3.8(s,3H),6.35(d,1H),7.21–7.25(m,1H),
7.60-7.65(m,2H),8.01-8.05(m,1H)。
Step 2：(1H- indoles -1,7- diyls) dimethanol
At 0 DEG C, to the tetrahydrochysene of 1- (tertiary butyl) -7- Methyl-1H-indoles -1,7- dicarboxylic ester (7.50g, 0.027mol)
Lithium Aluminium Hydride (2.07g, 0.054mol) is added portionwise in furans (100mL), adds and slowly rises 50 DEG C of reaction half an hour of room temperature.Instead
It should finish, reaction solution is poured into trash ice and is saturated in the mixture of metabisulfite solution, stirs 15 minutes, is extracted with ethyl acetate three
Secondary, combined ethyl acetate phase is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, concentration.Excess carries out color through silicagel column
It composes purifying to be eluted with ethyl acetate/petroleum ether gradient (20-50%), obtains white solid product (2.40g, 50%).
1H NMR(400MHz,CDCl3,)δ4.5-4.55(m,3H),5.3(d,2H),6.30(d,1H),7.18–7.20(m,
1H),7.29(d,1H),7.40-7.43(m,1H),7.50-7.52(m,1H)。
Step 3：1H, 3H- [1,3] oxazines simultaneously [5,4,3- happinesses] indoles
At 0 DEG C, to (1H- indoles -1,7- diyl) dimethanol (2.40g, 0.014mol) and triphenylphosphine (4.26g,
Diisopropyl azodiformate (3.29g, 0.016mol) is added dropwise in anhydrous tetrahydro furan (50mL) 0.016mol), adds liter
Room temperature reaction is overnight.Reaction finishes, and is concentrated under reduced pressure, and residue adds water to be extracted with ethyl acetate three times, combined ethyl acetate phase, uses
Saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentration.Excess carries out chromatogram purification ethyl acetate/stone through silicagel column
Oily ether gradient (10-20%) elution, obtains white solid product (1.50g, 69.6%).
1H NMR(400MHz,CDCl3,)δ4.50(s,3H),5.6(s,2H),6.40(d,1H),7.15–7.19(m,1H),
7.31(d,1H),7.42-7.45(m,1H),7.53-7.55(m,1H)。
Therapeutic effect of 2 drug of the present invention of experimental example for canker sore
2% yellow Jackets anaesthetize female sd inbred rats 30, the use of bore are Pasteur's pipe that cotton is plugged in 5mm and nozzle
Saturation sodium hydroxide solution is drawn, Pasteur's nozzle is affixed on the cheek mucous membrane of rat, duration 60s.Rat left and right sides cheek
Mucous membrane does same treatment.Modeling visually observes afterwards for 24 hours, and rat mucous membrane of mouth forms the ulcer of a diameter about 5mm.In ulcer
There is the covering of yellow-white pseudomembrane on centre recess, surface, around has bleeding and with congestion and edema.HE dyes visible mucosal epithelium and falls off, Gu
There is layer to have inflammatory cell infiltration, display modeling success.After modeling, rats with left ulcer surface applies 0.1mg/kg glycerine, is glycerine pair
According to group, right side ulcer surface applies 1 drug 0.1mg/kg of embodiment to ulcer surface, is medicine group of the present invention, is administered three times a day.Respectively
In 0,2,4,6,8 day random each 6 of rat of execution of administration, ulcer mucous membrane and muscle layer are completely removed, vernier caliper measurement, which calculates, bursts
Ulcer area.Tissue block makes paraffin section, and HE dyeing, Use immunohistochemistrySP SP detects the fibroblast factor 1 (FGF1) and α is smooth
Expression (the FGF1 antibody mabs of flesh actin (α-SMA)：Santa Cruz companies of the U.S.；α-SMA antibody mabs：Denmark
DAKO companies), measure the expression of average optical density value semi-quantitative western using Image-ProP1us6.0.
Using SPSS19.0 softwares, measurement data mean ± standard deviationIt indicates, is examined using variance analysis, t,
P<0.05 is statistically significant for difference.
Two groups of rat different time canker sore areas compare
After modeling, glycerol control group and the area of medicine group rat canker sore of the present invention are constantly reduced.Administration 0 day, 2 days
Glycerol control group and medicine group ulcer area no significant difference of the present invention, the medicine group ulcer surface of the present invention after being administered 4 days, 6 days
Product is less than control group, the statistically significant (P of difference<0.05) 8 days two groups of mucous membranes, are administered to heal, see Fig. 1.
Immunohistochemistry
Medicine group FGF1 expression of the present invention in the 6th, 8 day is apparently higher than glycerol control group (P after administration<0.05).After administration
4, the expression of 6,8 days α-SMA is apparently higher than glycerol control group (P<0.05) the 6th day expression highest, is administered, expresses within the 8th day
Declined.FGF1 and α-SMA have a different degrees of expression in each layer of mucous membrane, wherein epithelium basal layer and lamina propria expression compared with
It is more, see Fig. 2 and Tables 1 and 2.
1 two groups of canker sore rat FGF1 expression of table (average optical density value,
Note：Compared with glycerol control group, * P<0.05.
2 two groups of canker sore rat α-SMA expression of table (average optical density value,)
Note：Compared with glycerol control group, * P<0.05.
Claims (2)
1. a kind of preparation method of pharmaceutical composition that treating canker sore, this method include the following steps：
Step A：At 0 DEG C, into indoles 7- methyl formates and the dichloromethane and triethylamine mixed solution of 4-dimethylaminopyridine
Di-tert-butyl dicarbonate is added dropwise, adds liter room temperature reaction overnight, reaction finishes, and water is added, and three times with dichloromethane extraction, merges
Dichloromethane phase, is washed with saturated nacl aqueous solution, and anhydrous sodium sulfate drying is concentrated to give 1- (tertiary butyl) -7- methyl-1s H-
Indoles -1,7- dicarboxylic esters
Step B：At 0 DEG C, tetrahydrochysene is added into the tetrahydrofuran of 1- (tertiary butyl) -7- Methyl-1H-indole -1,7- dicarboxylic esters
Aluminium lithium adds and slowly rises 50 DEG C of reaction half an hour of room temperature, and reaction finishes, and reaction solution is poured into trash ice and is saturated metabisulfite solution
In mixture, stirs 15 minutes, be extracted with ethyl acetate three times, combined ethyl acetate phase is washed, nothing with saturated nacl aqueous solution
Aqueous sodium persulfate is dried, concentration, and excess carries out chromatogram purification ethyl acetate/petroleum ether gradient 20-50% through silicagel column and elutes, and obtains
To white solid product (1H- indoles -1,7- diyls) dimethanol
Step C：At 0 DEG C, to azo is added dropwise in the anhydrous tetrahydro furan of (1H- indoles -1,7- diyl) dimethanol and triphenylphosphine
Dioctyl phthalate diisopropyl ester adds liter room temperature reaction overnight, and reaction finishes, and is concentrated under reduced pressure, and residue adds water to be extracted with ethyl acetate
Three times, combined ethyl acetate phase is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, concentration, and excess is carried out through silicagel column
Chromatogram purification with ethyl acetate/petroleum ether gradient 10-20% elute, obtain white solid product 1H, 3H- [1,3] oxazines simultaneously [5,
4,3- is liked] indoles
2. the preparation method of the pharmaceutical composition for the treatment of canker sore according to claim 1, this method further includes following
Step：One or more pharmaceutically acceptable carriers can be added as needed, such as diluent, excipient, filler, absorption
Accelerating agent, surfactant etc., and the dosage form of needs is made.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810334362.2A CN108659003B (en) | 2018-04-14 | 2018-04-14 | Preparation method of compound for treating oral ulcer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810334362.2A CN108659003B (en) | 2018-04-14 | 2018-04-14 | Preparation method of compound for treating oral ulcer |
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| CN108659003A true CN108659003A (en) | 2018-10-16 |
| CN108659003B CN108659003B (en) | 2021-01-26 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015191A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Multicyclic lonidamine analogs |
| CN102307868A (en) * | 2009-02-04 | 2012-01-04 | 詹森药业有限公司 | Indole derivatives as anticancer agents |
| WO2012003338A1 (en) * | 2010-07-01 | 2012-01-05 | Takeda Pharmaceutical Company Limited | COMBINATION OF A cMET INHIBITOR AND AN ANTIBODY TO HGF AND/OR cMET |
-
2018
- 2018-04-14 CN CN201810334362.2A patent/CN108659003B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015191A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Multicyclic lonidamine analogs |
| CN102307868A (en) * | 2009-02-04 | 2012-01-04 | 詹森药业有限公司 | Indole derivatives as anticancer agents |
| WO2012003338A1 (en) * | 2010-07-01 | 2012-01-05 | Takeda Pharmaceutical Company Limited | COMBINATION OF A cMET INHIBITOR AND AN ANTIBODY TO HGF AND/OR cMET |
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| Publication number | Publication date |
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| CN108659003B (en) | 2021-01-26 |
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